Abstract: Recent studies of biopsy derived normal adult human tau indicate that these proteins are phosphorylated at nearly all of the sites previously identified as "abnormal" in paired helical filament (PHF) tau (PHF-tau) in the brains of Alzheimer's disease (AD) patients with or without cortical Lewy bodies (LBs), and in the brains of Parkinson's disease (PD) patients who become demented and show postmortem evidence of PD and AD (PD/AD). Thus, neurofibrillary tangles (NFTs) and related lesions composed of PHF-tau are characteristic of AD with or without an associated LB disorder. In contrast to PHF-tau, biopsy derived normal human tau can be induced at room temperature to undergo rapid and selective dephosphorylation at many of the so-called "abnormal" sites that are retained in PHF-tau. These provocative observations mandate a re-assessment of prevailing views about the pathogenesis of PHF-tau, and they imply that previously described differences in the phosphorylation sites and/or state of autopsy derived normal human tau versus PHF-tau reflect the differential activities of phosphatases in the postmortem control versus AD brain. Indeed, protein phosphatase 2A (PP2A) has been implicated in the failure of PHF-tau to undergo efficient dephosphorylation, and the down-regulation of PP2A could lead to the accumulation of PHF-tau in neurofibrillary lesions in AD, the LB variant of AD (LBVAD) and PD/AD. Since heterotrimeric (i.e. A, B and C subunits) but not heterotrimeric (i.e. A and C subunit) PP2A effectively dephosphorylates tau, alterations in the accessory, catalytic and regulatory subunits of PP2A could play a central role in the generation of PHF-tau. To pursue this hypothesis, this project will: 1.) Compare the sites and extent of phosphorylation in PHF-tau and biopsy derived normal human tau; 2.) Develop antibodies to each subunit heterotrimeric PP2A, and localize them in the brains of controls and patients with AD, the LBVAD and PD/AD; 3) Compare levels of heterotrimeric and heterotrimeric PP2A in the same group of brains; 4.) Characterize the repertoire of PP2A subunits in human biopsy brain samples; 5.) Assess changes in the mRNA levels of PP2A subunits in normal neurons and adjacent tangle bearing neurons in the brains of patients with AD, the LBVAD and PD/AD. These studies will provide important insights into the role of phosphatases in the pathogenesis of PHF-tau in AD and PD/AD.